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PML activates transcription by protecting HIPK2 and p300 from SCFFbx3-mediated degradation

Yutaka Shima1, Takito Shima, Tomoki Chiba

  • 1Molecular Oncology Division, National Cancer Center Research Institute, Tokyo, Japan.

Molecular and Cellular Biology
|September 24, 2008
PubMed

Insights

The PML protein stabilizes transcription factors HIPK2 and p300 by preventing their degradation via the SCF(Fbx3) ubiquitin ligase, thereby activating transcription. Leukemia-associated PML-RARalpha, however, promotes HIPK2 degradation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The promyelocytic leukemia (PML) protein is known to interact with transcription factors and coactivators like HIPK2 and p300, facilitating transcriptional activation.
  • The precise molecular mechanisms by which PML stabilizes transcription factor complexes remain largely unelucidated.

Purpose of the Study:

  • To elucidate the molecular mechanism of PML in transcription regulation.
  • To identify novel components of the PML complex and their roles in protein degradation and transcription.

Main Methods:

  • Purification of the PML complex to identify associated proteins.
  • Characterization of the SCF(Fbx3) ubiquitin ligase complex and its substrates.
  • Investigation of the ubiquitination and degradation pathways of HIPK2 and p300.
  • Analysis of the synergistic transcriptional activation of p53 by PML, Fbx3, and HIPK2.

Main Results:

  • The PML complex contains Fbxo3 (Fbx3), Skp1, and Cullin1, forming the SCF(Fbx3) ubiquitin ligase.
  • SCF(Fbx3) promotes the degradation of HIPK2 and p300 via the ubiquitin-proteasome pathway.
  • PML inhibits HIPK2 and p300 degradation without affecting their ubiquitination.
  • PML, Fbx3, and HIPK2 synergistically enhance p53-induced transcription.
  • The leukemia-associated fusion protein PML-RARalpha induces HIPK2 degradation.

Conclusions:

  • PML stabilizes transcription factor complexes by protecting HIPK2 and p300 from SCF(Fbx3)-mediated degradation, ensuring transcriptional completion.
  • Dysregulation of HIPK2 degradation by PML-RARalpha may contribute to leukemogenesis.
  • The interplay between PML, Fbx3, HIPK2, p300, and ubiquitination is crucial for transcriptional regulation and has implications in leukemia.

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